2-alkanoyl,alkanoylalkyl,alkanoyloxyalkyl,and hydroxyalkyl substituted tetrahydro - halo - sulfamyl- quinazolinones



3,549,636 Patented Dec. 22, 1970 United States Patent Oin'ce 3,549,636 Z-ALKANOYL, ALKANOYLALKYL, ALKANOYL- OXYALKYL, AND HYDROXYALKYL SUBSTI- TUTED TETRAHYDRO HALO SULFAMYL- QUINAZOLINONES Bola Vithal Shetty, Rochester, N.Y., assignor to Pennwalt Corporation, East Orange, N.J., a corporation of Pennsylvania No Drawing. Filed Feb. 29, 1968, Ser. No. 709,184 The portion of the term of the patent subsequent to Dec. 26, 1984, has been disclaimed and dedicated to the Public Int. Cl. C07d 51/48 US. Cl. 260-2565 8 Claims ABSTRACT OF THE DISCLOSURE A l,2,3,4-tetrahydro-7-halo-6=sulfamy1-4-quinazolinone compound, characterized by having in the 3-position an aryl or aralkyl group, and by having in the 2-position an alkanoyl, alkanoylalkyl, hydroxyalkyl or an alkanoyloxyal-kyl (a loweraliphatic ester of a hydroxyalkyl). These compounds have diuretic characteristics.

This invention relates to 1,2,3,4-tetrahydro-6-sulfamyl- 4-quinazolinone compounds.

Diuretic compounds of the above type have been made, having a hydroxyalkyl group in the 2-position (see US. Pat. 3,214,429) but improvements in the diuretic and saluretic properties of such compounds were desired.

In accordance with this invention 1,2,3,4-tetrahydro-7- halo or 7-haloalkyl-6-sulfamyl 4 quinazolinone compounds have in the 3-position an aryl or aralkyl group and in the 2-position an alkanoyl, alkanoylalkyl, hydroxyloweralkyl or an alkanoyloxyloweralkyl. These compounds are improved diuretics.

The compounds of this invention are preferably of the following formula:

or pharmaceutically acceptable salts thereof, in Which X is halogen or trifluoromethyl; R is hydrogen or lower-' or-loweralkyL CHJoweralkyl C O -lowera1ky1 R is hydrogen, loweralkyl, loweralkoxy, loweralkoxyalkyl, amino, sulfamyl, halogen, trifluoromethyl or hydroxy; R and R are any of R R and R are hydrogen, loweralkyl or phenylloweralkyl, and n is an integer from 0-4.

In the above formula X is preferably chlorine or trifiuoromethyl, but bromine and other halogens are not precluded. R is preferably hydrogen, but loweralkyls, such as methyl, ethyl, and propyl may be used. R is preferably hydroxymethyl, hydroxyethyl or acetyl. R R and R may be any of the stated radicals in the ortho, meta or para postions. Preferably R is methyl in the ortho position; also Where sulfamyl is used it is preferably present in the meta or para position with methyl in the ortho position.

Specific suitable compounds of the above formula includer 2-acetyl-7-c'hloro-6-sulfamyl-3 -(o--tolyl)-1,2,3,4-tetrahydro-4-quinazolinone; 2-acetyl-7-trifiuoromethyl-6-sulfamy1-3 -(o-tolyl) -1,2,3,4-

tetrahydro-4-quinazolinone; 2-acetyl-7-chloro-6-sulfamyl-3 -phenyl-1,2,3,4-tetrahydro- 4-quinazolinone; 2-acetyl-7-chloro-6-sulfamyl-3-(p-tolyl) -1,2,3,4-tetrahydro-4-quinazolinone; 2-acetyl-7-chloro-6-sulfamy1-3-(m-tolyl)-1,2,3,4-tetrahydro-4-quinazolinone; 2-acetyl-7-trifluoromethyl-6-sulfamy1-3-(p-tolyl) -1,2,3 ,4-

tetrahydro-4-quin azolinone'; 2-p ropionyl-3 -phenyl-6-sulfamyl-7-chloro-1,2,3 ,4-tetrahydro-4-quina2olinone; 2-propionyl-3-(o-tolyl)-6-sulfamyl-7-chloro-1,2,3 ,4-tetrahydro-4-quinazolinone; 2-acetyl-7-chloro-6-methylsulfamyl-3- (o-tolyl) -1,2,3,4-

tetrahyd ro-4-quinazolinone; 2-acetyl-7-chloro-6-dimethylsulfamy1-3- o-tolyl) 1 ,2,3 ,4-

tetrahydro-4-quinazolinone; 2-propionyl-7-chloro-6-methylsulfamyl-3 -phenyl- 1,2, 3 ,4-

tetrahyd ro-4-quinazolinone; 2-acetyl-3- (p-chlorobenzyl -6-sulfamyl-7-trifluorornethyl- 1,2, 3 ,4-tetrahyd ro -4-quinazolinone; 2-propionyl-3 p-chlorobenzyl) -6-sulfamyl7-trifiuoromethyl-1,2, 3 ,4-tetrahydro@4-quinazolinone; Z-acetylrnethyl-7-chloro-6-sulfamyl-3 -(o-tolyl) -1,2,3,4-

tetrahydro-4quinazolinone; 2-acetylmethyl-7-chloro-6-sulfamyl-3 -phenyll ,2,3 ,4-

tetrahydro-4-quinazolinone 2-acetylmethyl-7-chloro-6-methyls-ulfamy1-3 (o-tolyl) 1,2,3,4-tetrahydro-4-quinazolinone; 2-acetyl-7-chloro-6-sulfamyl-3- (2-methyl-5 '-sulfamyl) 1,2,3,4-tetrahydro-4-quinazolinone; 1-benzy1-2-acetylmethyl-7-chloro-6 -sulfamyl-3 -phenyl- 1,2, 3 ,4-tetrahydro-4-quinazolinone; 2-acetylmethyl-7-dhloro-6-b enzylsulfamy1-3 -phenyl- 1,2,3 ,4-tetrahydro-4-quinazolinone; Z-B-hydroxybutyl-7-chloro-6-sulfamyl-3 (o-tolyl) 1,2,3 ,4-tetrahydro-4-quinazolinone; 2-acetyloxymethy1-7-chloro-6-sulfamyl-3 (o-tolyl 1,2,3 ,4-tetrahydro-4-quinazolinone; 2-acetyloXymethyl-7-trifluorometh yl--methylsulfamyl- 3 -phenyl-1,2,3 ,4-tetrahydro-4-quinazolinone;

1-methyl2/8-hydroxypropyl-7-chloro-6-sulfamyl-3- 8 TABLE lCutinued R1 R2 R3 X R1 TL R4 R5 H CHZCOCZH5 2-Me CF; 0 H H H I H H 01120002115 2-Mo CF; -CzH5 1 H H H Q-g- 0112000211 H 01 H 0 n u The following example is given to illustrate the preparation of compounds of this invention: H 0 PREPARATION OF 2-AOETYL-7-CHLORO-6-SUL- /N HALCHS FAMYL-B-(O-TOLYL) 1,2,3,4 TETRAHYD'RO-4- QUINAZOLINONE HzNOzS Synthetic route 1] y 01- NH 01- NHAc 2 A020 1. ClSOaH CH3 -on2 CH3 The other compounds of this invention can be made by modification of ingredients and quantities of the above example as is well understood by those skilled in the C1 NHAC KM1O4 Cl NHAG NaOH art. For example, the unsaturated quinazolinone com- HNOS HNO COOH pounds can be readily converted to the corresponding 2 2 2 2 1,2,3,4-tetrahydro-4(3H) quinazolinones by reduction with sodium borohydride. From pharmacology tests run on 2-acetyl-3-o-tolyl- 6-sulfamyl-7-chloro-1,2,3,4 tetrahydro 4(3H) quin- 21 azolinone and other indications and analogy, it appears H2N02S COOH that the compounds of this invention are effective diuretics, saluretics, and antihypertensives with low toxicity. For example, the following is a summary of the CH3 pharmacology on the above compound. H SUMMARY 01 N\ Q-NHZ 0:0 (a) Symptomatology and Acute LDSO in mice:

' Orally-LD 1000 mg./kg. 48 hours) H NO s- O 4,,

z 2 Interper1tonea1-LD50 316 mg./kg. (48 hours) ll (b) Cardiovascular in dog: Doses intravenously up to 10 mg./kg. were administered. There were no changes in the cardiovascular system. 50 (c) Diuretic assay in rats: When administered by the c1 NH, oral route in initial assays measuring output of urine W (ml./kg.), Na+, and c1- (meq./kg.) at 4 hours and HzNOzS- c ONE-Q HzSOt/HOAO 21 hours after drug administration, the compound was I found to promote water and salt loss, has a rapid onset CH; and prolonged action, and appears to have a potency 1, 5-Diazobieyclo [4.3.0] nonaue DMCO on volume diuresis better than that of quinethazone.

From the above and other tests, applicant states that the compounds described in this specification and those coming under the generic formula are effective and safe diuretics when administered to warm-blooded animals in the same manner and amounts as for quinethazone.

In the preceding specification the temperatures, wherever given, are in degrees centigrade.

Various modifications of the structural formula on column 1 of the specification may be made, such as, for example, has been done for other tetrahydro-7-halo-6- sulfamyl-4-quinazolinones known to the art, Without departing from the spirit of the invention which is concerned particularly with diuretic quinazolinone compounds with the aryl and alkaryl group on the 3-positiun, and the group in the 2-position as indicated in the generic structural formula.

It will also be understood that any of the groups of R may be substituted for the Z-hydrogen of the heterocycle to give a di compound or a spiro compound.

Likewise, therapeutically effective salts of the compounds of the invention may be made by methods known to the art, and are useful diuretics. For example, the sulfamyl group will react with bases to give sodium, potassium or ammonium salts of the quinazolinone compound. The basic nitrogen of the quinazolinone can be reacted with acids such as hydrochloric, maleic, tartaric, and the acidic ion exchange resins such as carboxylic acid, phosphonic acid, and sulfonic acid cation exchange resins to give the therapeutically effective and nontoxic salts of the quinazolinone compound.

I claim:

1. A compound of the formula:

or the pharmaceutically acceptable salts thereof, in which X is halogen or trifluoromethyl; R is hydrogen or loweralkyl; R is loweralkanoyl, loweralkanoylloweralkyl, hydroxyloweralkyl, or a loweralkanoyloxyJoweralkyl; R is hydrogen, loweralkyl, loweralkoxy, loweralkoxyalkyl, hydroxy, amino, sulfamyl, halogen or trifiuoromethyl; R and R are any of the members of R R and R ar hydrogen, loweralkyl or phenylloweralkyl, and n is an integer from 0-4.

2. The compound of claim 1 wherein X is chlorine,

R is hydrogen, R is loweralkanoyl, R is ortho-metbyl, R R R and R are hydrogen, and n is 0.

3. The compound of claim 1 wherein X is chlorine, R is hydrogen, R is acetyl, R is ortho-methyl, R R R and R are hydrogen, and n is 0.

4. The compound of claim 1 wherein X is chlorine, R is hydrogen, R is hydroxyloweralkyl, R is orthomethyl, R R R and R are hydrogen, and n is 0.

5. The compound of claim 1 wherein X is chlorine, R is hydrogen, R is loWeralkanoyloxylloweralkyl, R is ortho-methyl, R R R and R are hydrogen, and n is 0.

6. The compound of claim 1 wherein X is trifluoromethyl, R is hydrogen, R is loweralkanoylloweralkyl, R is ortho-methyl, R R R and R are hydrogen, and n is 0.

7. The compound of claim 1 wherein the pharmaceutically acceptable salt is an alkali metal salt.

8. The compound of claim 1 in which the compound is in base form.

References Cited UNITED STATES P'ATENTS 3,092,631 6/1963 Song et al. 260256.5 3,214,429 10/1965 Uskokovic et al. 260256.5 3,360,518 12/1967 Snetty 2602S6.5

ALEX MAZEL, Primary Examiner R. J. GALLAGHER, Assistant Examiner U.S. Cl. X.R. 424-79, 25 

